Selective expression and functional characteristics of three mammalian hyaluronan synthases in oncogenic malignant transformation.

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  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Print ISSN: 0021-9258 (Print) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Gene Expression Regulation, Neoplastic*; Cell Transformation, Neoplastic/*metabolism ; Glucuronosyltransferase/*metabolism; Animals ; Base Sequence ; Cell Line, Transformed ; Glucuronosyltransferase/genetics ; Glucuronosyltransferase/physiology ; Hyaluronan Synthases ; Hyaluronic Acid/biosynthesis ; Hyaluronic Acid/physiology ; Mice ; Molecular Sequence Data ; Neoplasms, Experimental/etiology ; Neoplasms, Experimental/pathology ; Oligonucleotides, Antisense/pharmacology ; RNA, Messenger/analysis ; Rats ; Transfection ; Transferases/genetics ; Transferases/metabolism ; Transferases/physiology ; Up-Regulation
    • Abstract:
      Malignant transformation of fibroblasts and epithelial cells is often accompanied by increased hyaluronan production and accumulation. Despite recent progress in the study of hyaluronan biosynthesis, the mechanisms underlying the transformation-induced overproduction of hyaluronan have not been elucidated. Here we report that activity and transcriptional levels of hyaluronan synthase (HAS) significantly increased after oncogenic malignant transformation of a rat 3Y1 fibroblast cell line. Of three HAS isoforms (HAS1, HAS2, and HAS3), only HAS2 gene expression was increased in the v-Ha-ras transformed 3Y1 cells, which show less malignancy. In contrast, both HAS1 and HAS2 expressions were elevated in the highly malignant cells transformed with v-src and/or v-fos. To assess the contribution of HAS expression to the oncogenic malignant transformation, we established stable cell transfectants expressing sense and antisense HAS genes. Antisense suppression of the HAS2 expression significantly decreased hyaluronan production in the cells transformed by the oncogenic v-Ha-ras and eventually led to a reduction in tumorigenicity in the rat peritoneum. The introduction of the HAS1 and HAS2 genes promoted the growth of subcutaneous tumors in a manner dependent on the levels of hyaluronan synthesis. Significant growth promotion was observed within a wide range of HAS1 expression. In contrast, the growth stimulation was only seen within a narrow range of HAS2 expression, and high levels of HAS2 expression even inhibited tumor growth. These results suggest that proper regulation of the expression of each HAS isoform is required for optimal malignant transformation and tumor growth.
    • Molecular Sequence:
      GENBANK AB097568; AB097569
    • Accession Number:
      0 (Oligonucleotides, Antisense)
      0 (RNA, Messenger)
      9004-61-9 (Hyaluronic Acid)
      EC 2.- (Transferases)
      EC 2.4.1.17 (Glucuronosyltransferase)
      EC 2.4.1.212 (Has3 protein, mouse)
      EC 2.4.1.212 (Has3 protein, rat)
      EC 2.4.1.212 (Hyaluronan Synthases)
    • Publication Date:
      Date Created: 20040116 Date Completed: 20040610 Latest Revision: 20210206
    • Publication Date:
      20221213
    • Accession Number:
      10.1074/jbc.M313178200
    • Accession Number:
      14724275